Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that contains both thiol-protein oxidoreductase activity and tautomerase/isomerase activity. MIF is released by T-cells and macrophages and modulates not only macrophage functions, but also T cell functions (Kitaichi et al., Immunobiology, 2000. 201 (3-4): p. 356-67). MIF is viewed to play a role in a wide range of diseases including, cancer, rheumatoid arthritis, sepsis, atherosclerosis, colitis, lupus, asthma, acute respiratory distress syndrome and acute graft-versus-host disease. MIF is involved in cellular proliferation and differentiation and has been demonstrated to have protumorigenic activity. MIF expression in tumors is thought enhance the aggressiveness and metastatic potential of tumor cells. MIF is overexpressed in many tumors, including breast, ovarian, colon and prostate cancer, melanoma, cervical cancer, gastric cancers, hepatocellular carcinoma, and glioblastomas (Hagemann et al., 2007, Mol. Cancer Ther., 6, 7, 1993-2002; Akbar et al., 2001, Cancer Lett., 171, 2, 125-32, Kamimura et al., 2000, Cancer, 89, 2, 334-41; Xu et al., 2008, Cancer Lett., 261, 2, 147-57; Munaut et al., 2002, Neuropathol Appl. Neurobiol., 28, 6, 452-60; Bacher et al., 2003, Am. J. Pathol., 162, 1, 11-7; and Meyer-Siegler et al., 2002, Cancer, 94, 5, 1449-56).
The over-expression of macrophage migration inhibitory factor (MIF), and/or MIF receptor/s (CD74 and CXCR4) is observed in premalignant, malignant, and metastatic tumors. This over-expression is observed in cancers including non-small cell lung cancers (Gamez-Pozo et al., PLoS One, 7, 3, e33752; and McClelland et al., 2009, Am. J. Pathol., 174, 2, 638-46). Cancer cells over-expressing CD74 can import approximately ˜107 molecules of an anti-CD74 mAb (LL1) per cell per day (Hansen et al., 1996, Biochem. J., 320 (Pt 1), 293-300). The surface half-life of the CD74 may be less than ten minutes (Starlets et al., 2006, Blood, 107, 12, 4807-16).
Analyses of an MIF knockout mouse model and the use of anti-MIF antibodies to modulate MIF levels have demonstrated MIF involvement in cancer and inflammation. MIF may play a role in the progression to more invasive tumors and MIF may control the tumor spectrum mediating a shift in frequency between T-cell lymphomas, fibrosarcomas and B-cell lymphomas (Bernhagen et al Nature Med., 2007. 13(5): p. 587-96 and Taylor et al. BMC Cancer, 2007. 7: p. 135.). De Jong and associates showed that Murine colitis is dependent on continuous MIF production by the immune system. Both ulcerative colitis (UC) and Crohn's colitis patients are at increased risk of developing colorectal cancer (De Jong et al. Nature Immunol., 2001. 2(11): p. 1061-6 and Itzkowitz and Yio, Am. J. Physiol Gastrointest. Liver Physiol., 2004. 287(1): p. G7-17) used mice knocked out both for MIF and a second gene causing T-cell deficiency. Colitis was shown to be dependent on MIF produced by non-lymphocyte hematopoetic cells.
MIF circulates normally in human plasma at high levels of 2-6 ng/ml (Stosic-Grujicic et al. Autoimmun. Rev., 2009. 8(3): p. 244-9) and these levels can be increased in disease states including many cancers. In sepsis, levels of MIF may be elevated more than 100 fold over basal level (Emonts et al., Clin. Infect. Dis., 2007. 44(10): p. 1321-8).
A major problem in most forms of cancer chemotherapy is the severe non-specific toxicity chemotherapeutic drugs may also have against rapidly-dividing cells and healthy tissues. These side effects often result in dose reduction, treatment delay or discontinuance of therapy. Targeted drug delivery systems have been developed to try to circumvent these side effects, using targeting agents such as receptor ligands, sugars, lectins, antibodies, antibody fragments, hormones, and hormone analogues. Therefore, there is a need in the art to better target cytotoxic moieties into those areas of cancer cells where the toxic moiety can better exert its pharmacologic influence.